This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. Oral cancer patients comprise about 5% of the cancer population in the United States, and their overall survival rate has not improved substantially during the last 20 years. The factors involved in the etiology of the majority of oral cancers include alcohol and tobacco use and infection with human papillomavirus (HPV). The relative accessibility of the tumors makes them attractive candidates for local treatment using gene therapy approaches. The overall goal of this project is to determine if the p53 and retinoblastoma (RB) tumor suppressor genes can be exploited in genetic manipulation of oral cancer. These genes were chosen because the transforming proteins E6 and E7 of the oncogenic HPVs bind to and functionally inactivate the p53 and RB (pRB) proteins, respectively. This study will begin to define the role of these two tumor suppressor proteins in oral carcinogenesis and determine if the genes coding for these proteins are suitable targets for gene therapy. Oral squamous cell carcinomas, both HPV-positive and HPV- negative will be examined for mutations in the p53 and RB genes. In vitro studies will be done to determine if the addition of exogenous p53 and pRB, introduced into oral cancer cells via an inducible expression vector, can overcome the effects of the HPV transforming proteins and/or p53 and RB mutations, reverting the cells to a non-malignant phenotype. Various parameters of cell transformation will be measured as will the ability of the cells to form tumors in nude mice. Changes in proliferation and differentiation markers will also be measured.